1. Field of the Invention
This invention relates to a method for the treatment of damage to the blood-forming function of the bone marrow of a living mammal. An aspect of this invention relates to the treatment of bone marrow which has been damaged as a result of the undesirable side effects of anti-cancer treatments or the like, particularly damage caused by the bone marrow toxicity of anti-cancer drugs. Another aspect of this invention relates to the alleviation of the dose-limiting aspects of certain clinical treatments, particularly anti-cancer treatments in which the blood-forming function of the bone marrow is impaired. A still further aspect of this invention relates to unit dosages for the parenteral administration of compounds found to be effective in restoring, at least partially, the blood-forming function of bone marrow damaged by clinical treatments for cancer or other diseases.
2. Background of the Invention
At least as far back as the early 1970's, it was found that dithiocarbamates and their dimers (e.g. disulfiram) are clinically-useful compounds of relatively low toxicity toward mammals. One of the early uses of sodium diethyldithiocarbamate was in the treatment of acute nickel carbonyl poisoning. See S. William Sunderman, Ann. Clin. Res. 3:182-185 (1971). The diethyldithiocarbamate dimer, disulfiram has been used to treat alcoholism. More recently, dithiocarbamates or their dimers have been used to inhibit the undesirable side effects of platinum compounds such as the square planer platinum (II) complexes used as antineoplastic agents. See U.S. Pat. No. 4,426,372 (Jan. 17, 1984), 4,594,238 (June 10, 1986), and 4,581,224 (Apr. 8, 1986), all issued to R. F. Borch. For a discussion of the types of platinum-containing drugs contemplated by Borch for use in combination with these dithiocarbamic compounds, see (in addition to the three Borch patents) U.S. Pat. Nos. 4,053,587 (Davidson et al), issued Oct. 11, 1977, 4,137,248 (Gale et al), issued Jan. 30, 1979, 4,562,275 (Speer et al), issued Dec. 31, 1985, 4,680,308 (Schwartz et al), issued July 14, 1987, and similar references appearing in both the patent and scientific literature, e.g. the series of papers regarding platinum treatment of tumors and resulting side effects in Cancer Treatment Reports, volume 63 (1979), beginning at page 1433. The platinum compounds useful as antineoplastic agents are not limited to platinum (II) compounds, because it has been found that platinum (IV) compounds can be administered in much the same manner as platinum (II) compounds, apparently because these six-ligand complexes break down in vivo to square planar complexes of the platinum (II) type.
The Borch method of, for example, U.S. Pat. No. 4,426,372 has been shown to be effective in clinical trials. That is, this method reduces substantially the side effects of platinum-containing drugs. These side effects include both kidney toxicity and bone marrow toxicity. The mechanism by which dithiocarbamic compounds protect against or reduce the kidney toxicity has been studied extensively by Borch and his co-workers and has even been simulated accurately with in vitro studies. Accordingly, this mechanism is relatively well understood. To reverse or prevent kidney toxicity, the dithiocarbamic compound is administered after the platinum-containing drug has already begun to attack the tumor (the beneficial effect of the drug) and also has begun to attack critically important structures within the kidney (the undesirable side effect). The thus-administered dithiocarbamic compound does not reverse the tumor inhibition effects of the platinum drug, but it does displace platinum from these critical structures within the kidney, resulting in the formation of relatively harmless dithiocarbamate/Pt complexes, some of which are eliminated in the urine. This reversal of kidney damage appears to take place through a relatively straightforward chemical reaction requiring stoichiometric or nearly stoichiometric amounts of dithiocarbamic compound with respect to the amount of platinum tied up in the kidney. As a result, the effective dose of dithiocarbamic compound in the Borch method tends to reflect the stoichiometry of the situation and, for 5 mg/kg of intravenously administered platinum compound, the amount of dithiocarbamic "rescue agent", in mice, is likely to be in the range of 100 mg/kg to 400 mg/kg (intravenously) and can range as high as 750 mg/kg (intraperitoneally), also in mice. A dosage of less than 50 mg/kg of body weight of dithiocarbamate is not likely to be fully effective in providing relief from or prevention of kidney damage.
Although pharmaceutically acceptable dithiocarbamic compounds such as sodium diethyldithiocarbamate (NaDDTC) and disulfiram have relatively high LD.sub.50 values and are not considered highly toxic to mammals, there are scattered reports in the literature regarding strange behavior exhibited by rats or mice injected with NaDDTC. The true import of these scattered disclosures and suggestions in the literature became fully apparent during clinical trials of NaDDTC as a "rescue agent", i.e. as an agent for the reduction of side effects from the administration of platinum compounds. These clinical trials demonstrated that human patients given dosages of NaDDTC effective for "rescue" purposes (e.g. dosages on the order of 50-150 mg/kg of body weight) experienced extremely unpleasant effects which caused them to feel panic and discomfort. It was necessary to develop a technique of administration of the NaDDTC whereby the patient would be sedated prior to receiving the dithiocarbamate.
All available evidence indicates that the panic reaction to dithiocarbamates resulting from dosages of, for example, 50-150 mg/kg is not the result of any life-threatening process occuring in the body of the patient, nor is there any evidence of permanent or chronic effects or damage resulting from NaDDTC administration. After the course of dithiocarbamate administration has been completed, patients returned to normal and no sequellae of the panic reaction are observed. Moreover, it presently appears that some hydroxy-substituted analogs of NaDDTC may be even less toxic than NaDDTC itself.
Nevertheless, further improvement in the treatment of toxic side effects (e.g. treating the side effects of platinum compounds) is desirable.
As noted previously, much less is known about treatments for bone marrow toxicity. Some anti-cancer drugs, both platinum-containing and platinum-free, can seriously damage the blood-forming function of the bone marrow--an effect sometimes referred to as myelosuppression. Among the drugs causing significant myelosuppression effects are cytotoxic antibiotics and antibiotic derivatives, other cytotoxic drugs, antimetabolites (which inhibit processes involved in DNA formation), alkaloid-type anti-tumor agents, alkylating agents, and heavy metal complexes (particularly Pt complexes such as "Carboplatin"). A treatment for the side effects of these drugs would be a highly welcome addition to the field of cancer treatment.
Radiation therapy is still another potential source of serious damage to the blood-forming function of the bone marrow. Administration of various compounds (such as dithiocarbamates) has been studied as a preventative treatment for the side effects of radiation therapy.
Various sulfur-containing compounds including NaDDTC have been suggested as immunostimulant medicines. See U.S. Pat. No. 4,148,885 (Renoux et al), issued Apr. 10, 1979.